Safety and Efficacy of Tenofovir DF in HIV-1 Infected Adolescents Failing Their Current Antiretroviral Therapy

Safety and Efficacy of Tenofovir DF in HIV-1 Infected Adolescents Failing Their Current Antiretroviral Therapy

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of Tenofovir DF as Part of an Optimized Antiretroviral Regimen in HIV-1-Infected Adolescents

The purpose of this study is to assess the safety and efficacy of tenofovir disoproxil fumarate (tenofovir DF; TDF) plus a genotype-guided optimized background regimen (OBR) compared to placebo plus OBR in the treatment of human immunodeficiency virus type 1 (HIV-1) infected antiretroviral treatment-experienced adolescents with plasma HIV-1 ribonucleic acid (RNA) levels greater than or equal to 1000 copies/mL.

This is a 48-week, randomized, double-blind, placebo-controlled, multicenter study of the safety and efficacy of tenofovir DF as part of an optimized antiretroviral regimen in HIV-1 infected adolescents (12 years to < 18 years of age) who are failing their current antiretroviral regimen and have HIV-1 RNA levels ≥ 1000 copies/mL at screening. Data from three consecutive 96-week study extensions have been used to evaluate the long-term efficacy, safety, and tolerability of open-label tenofovir DF as part of an antiviral regimen, providing data for up to 336 weeks of total drug exposure. Pretreatment: HIV-1 genotyping will be performed as part of the screening assessments to assist in the construction of an OBR, defined as at least 3, but no more than 5 antiretroviral agents, not including tenofovir DF or placebo. Randomized Phase: Participants will be randomized in a 1:1 ratio to receive either tenofovir DF + OBR, or placebo + OBR. The majority of efficacy and safety assessments will be performed at each clinic visit (Weeks 4, 8, 16, 24, 32, 40, and 48). At Week 24, participants who are adherent to study drug (in the opinion of the investigator), but do not demonstrate a ≥ 0.5 log10 copies/mL decrease from baseline in HIV-1 RNA, will be considered to be nonresponders and will be unblinded. Nonresponders randomized to the placebo group will be given the option to continue on study and receive open-label tenofovir DF with an appropriate background regimen determined by the investigator. Nonresponders randomized to the tenofovir DF treatment group will be discontinued from the study. Extension Phases: After completing 48 weeks of double-blind treatment with tenofovir DF or placebo, participants who have not reached 18 years of age, and who, in the opinion of the investigator, would derive clinical benefit from the use of open-label tenofovir DF, will be given the option to continue (or initiate) treatment with open-label tenofovir DF in the first of three 96 week study extension periods. Nonresponders who receive open-label tenofovir DF after Week 24 will also be considered eligible for the first study extension if they met the above criteria at Week 48. After completing the first 96 week study extension, participants who have not reached 18 years of age, and who have shown ongoing clinical benefit from tenofovir DF, will be given the option to continue receiving open-label tenofovir DF for an additional 96 weeks or until tenofovir DF became commercially available in the country where the participants are enrolled, whichever occurs first. After completing the second 96 week study extension, participants who have not reached 18 years of age, and who have shown ongoing clinical benefit from tenofovir DF, will be given the option to continue receiving open-label tenofovir DF for an additional 96 weeks or until tenofovir DF became commercially available in the country where the participants are enrolled, whichever occurs first. Presentation of data: After the randomized phase of the study, participants randomized to placebo during the randomized phase of the study and then switch to open-label tenofovir DF will have their baseline reset (defined as open-label baseline), and only outcome data collected after (on/after for adverse events (AEs)/concomitant medications) participants receive their first dose of open-label tenofovir DF will be included.

Phase 3, Randomized, Double-Blind, Control, Treatment-Experienced, OBR, Optimized background regimen, Highly Active Antiretroviral Therapy, HAART, HIV, HIV-1, AIDS Virus, Human Immunodeficiency Virus, Acquired Immune Deficiency Syndrome Virus, Virus, Human Immunodeficiency, Pediatrics

DAVG24 was defined as the time-weighted average between the first postbaseline value through the last value up to Week 24 minus the baseline value. DAVG24 was calculated using the trapezoidal rule with all available postbaseline data minus the baseline value. Data for participants who discontinued the randomized (double-blind) phase of the study early were included up until the point of study discontinuation (missing data not imputed).

DAVG48 was defined as the time-weighted average between the first postbaseline value through the last value up to Week 48 minus the baseline value. DAVG48 was calculated using the trapezoidal rule with all available postbaseline data minus the baseline value. Data for participants who discontinued the double-blind phase of the study early were included up until the point of discontinuation from the study (ie, missing data were not imputed).

No analysis was performed because the last study participant discontinued after Week 294 and the study was closed.

No analysis was performed because the last study participant discontinued after Week 294 and the study was closed.

No analysis was performed because the last study participant discontinued after Week 294 and the study was closed.

Percentage of Participants With an HIV-1 RNA Decrease of ≥ 1.0 log10 Copies/mL From Baseline to Week 24

Percentage of Participants With an HIV-1 RNA Decrease of ≥ 1.0 log10 Copies/mL From Baseline to Week 48

Percentage of Participants With an HIV-1 RNA Decrease of ≥ 1.0 log10 Copies/mL From Baseline to Week 96

Percentage of Participants With an HIV-1 RNA Decrease of ≥ 1.0 log10 Copies/mL From Baseline to Week 144

Percentage of Participants With an HIV-1 RNA Decrease of ≥ 1.0 log10 Copies/mL From Baseline to Week 192

Percentage of Participants With an HIV-1 RNA Decrease of ≥ 1.0 log10 Copies/mL From Baseline to Week 240

Percentage of Participants With an HIV-1 RNA Decrease of ≥ 1.0log 10 Copies/mL From Baseline to Week 288

Percentage of Participants With an HIV-1 RNA Decrease of ≥ 1.0 log10 Copies/mL From Baseline to Week 336

No analysis was performed because the last study participant discontinued after Week 294 and the study was closed.

No analysis was performed because the last study participant discontinued after Week 294 and the study was closed.

No analysis was performed because the last study participant discontinued after Week 294 and the study was closed.

Virologic failure was defined as either nonresponse or viral rebound. Nonresponse (failure to achieve response). Response was defined as either A ≥ 0.5 log10 copies/mL decrease in HIV-1 RNA from baseline at 2 consecutive visits, or HIV-1 RNA < 400 copies/mL at 2 consecutive visits. Viral rebound was defined as either Participants who achieved a ≥ 0.5 log10 copies/mL decrease from baseline in plasma HIV-1 RNA at 2 consecutive visits, who then subsequently achieved plasma HIV-1 RNA values ≥ 1.0 log10 copies/mL above their on-study nadir (lowest value) and/or plasma HIV-1 RNA values ≥ the baseline value at 2 consecutive visits, or Participants who achieved plasma HIV-1 RNA levels of < 400 copies/mL at 2 consecutive visits, and then subsequently had plasma HIV-1 RNA levels > 1000 copies/mL at 2 consecutive visits. The virologic failure rate was estimated from Kaplan-Meier product limit method by including all HIV-1 RNA data collected during the double-blind phase.

Major Inclusion Criteria: Weight ≥ 35 kg Documented laboratory diagnosis of HIV infection Plasma HIV-1 RNA ≥ 1000 copies/mL Prior antiretroviral treatment experience with at least 2 antiretroviral drug classes Naive to tenofovir DF Absence of K65R mutation on genotypic testing Exclusion Criteria: Patients requiring didanosine in background regimen Prior history of significant renal disease Prior history of significant bone disease